Thyrotropin or thyroid-stimulating hormone (TSH) plays an important role in the regulation of metabolism and development. TSH is released from the anterior pituitary under the influence of thyrotropin—releasing hormone. It targets the thyroid gland to stimulate the release of the thyroid hormones triiodothyronine and thyroxine and thyroid growth. The actions of TSH are mediated by a specific G protein-coupled receptor which couples preferentially to Gs proteins leading to activation of adenylyl cyclase. This signal transduction pathway is predominantly responsible for the production of thyroid hormones and proliferation of the thyrocytes (Krohn et al. (2005) Endocrine Rev. 26, 504-524).
The TSH receptor on the thyroid is also directly involved in the pathogenesis and pathophysiology of Graves' disease. Graves' disease is characterized by hyperstimulation of the thyroid as a result of circulating TSH receptor-stimulating immunoglobulins (TSI), which persistently activate the receptor (Gerding et al. (2000) Clin. Endocrinol. 52, 267-271). TSI may also directly participate in the pathogenesis and pathophysiology of Graves' ophthalmopathy and Graves'-associated pretibial dermopathy as TSH receptors are present in orbital tissue and affected skin regions of these patients, respectively (Gerding et al. (2000) Clin. Endocrinol. 52, 267-271; Daumerie et al. (2002) Eur. J. Endocrinol. 146, 35-38). In addition, the TSH receptor plays a crucial role in toxic and non-toxic nodular goitre. In (toxic) nodular goitre, the thyroid gland contains autonomously functioning thyroid nodules that secrete excess thyroid hormone as a result of mutations in the TSH receptors which render them constitutively active with significantly increased cAMP levels (Krohn et al. (2005) Endocrine Rev. 26, 504-524).
Blocking the TSH receptor or inhibiting the signaling which is induced after TSH-, or TSI-mediated receptor stimulation, or as a result of constitutively active mutations of the TSH receptor will inhibit thyroid hormone secretion and thyrocyte proliferation. Low molecular weight TSH receptor antagonists could therefore be used to treat or prevent hyperthyroidism, Graves' disease, nodular goiter, Graves' ophthalmopathy and Graves'-associated pretibial dermopathy. In addition, low molecular weight TSH receptor antagonists could be used to prevent stimulation of growth of residues or metastases of thyroid cancer, which is thought to be promoted by (over)stimulation of the TSH receptor. In a more general sense, TSH receptor antagonists could be used to prevent or treat all of those ailments in which (over)activation of the TSH receptor plays a role.
Tetrahydroquinoline derivative compounds are described in WO2003/004028, WO2004/056779 and WO2004/056780. These compounds can be used to regulate fertility.
FSH receptor modulators reported in the literature have high specificity towards the FSH receptor. Yanofsky et at (2006, J. Biol. Chem. 281, 13226-13233) and Pelletier et at (2005, Bioorg. & Med. Chem. 13, 5986-5995) demonstrated that low nanomolar potent LMW FSH receptor agonists with a thiazolidinone scaffold are neither TSH recepotor antagonists nor agonists. Also (bis)sulfonic acid, (bis)benzamides, have been identified as FSH receptor antagonists, but they show no or little ability to inhibit TSH receptor activity (Wrobel et al., 2002, Biorg. Med. Chem. 10, 639-656). Another series of low micromolar FSH receptor antagonists (diazonapthylsulfonic acid derivatives) did not show affinity towards the TSH receptor (Arey et al., 2002, Endocrinology 143, 3822-3829).
In addition, mutagenesis studies on the FSH receptor and the TSH receptor have demonstrated that activation of the TSH receptor is distinct from that of the FSH receptor indicating that FSH receptor antagonists will not necessarily inhibit TSH receptor as well (Schulz et al., 1999, Mol Endocrinol 13, 181-190). This differential activation is underscored by the knowledge that the TSH receptor, in sharp contrast to the FSH receptor, also couples efficiently to phospholipase C via Gq proteins, a pathway which is required for thyroid hormone synthesis (Kero et al, 2007, J. Clin. Invest. 117, 2399-2407) and also activated by TSI in Graves' disease.